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July 15, 2005

Sleeping Beauty Plays a Significant Role in Identifying Cancer Genes

by Sam Savage

Researchers at the University of Minnesota Cancer Center and the National Cancer Institute (NCI), part of the National Institutes of Health, have discovered a new method that could accelerate the way cancer-causing genes are found and could lead to a more accurate identification of the genes, according to two studies in the July 14, 2005, issue of Nature*.

The gene identification method was developed in genetically modified mice and utilized a piece of jumping DNA, called Sleeping Beauty. Jumping genes, or transposons, insert themselves into or between genes and can activate or inactivate a gene's normal function. Related transposons are natural to the genetic makeup of humans, animals and fish, but, through millions of years of evolution, most transposons became inactive dead-ends. In 1997, in another study, University of Minnesota researchers took defunct, non-functioning jumping genes from fish and made the genes jump again. This research had reactivated the jumping genes from millions of years of evolutionary sleep; hence the name Sleeping Beauty.

In the two current research studies, specially designed Sleeping Beauty transposons were introduced into mouse DNA and made to jump around in the nucleus of mouse cells. Eventually the transposons jumped into cancer-causing genes and caused a tumor to form. By isolating and studying the genes from tumors that contained Sleeping Beauty, researchers were able to efficiently find genes linked to cancer by seeing whether Sleeping Beauty turned them on or off -- in effect, uncovering the fingerprint of each tumor's cancer genes.

David Largaespada, Ph.D., associate professor and leader of the Genetic Mechanisms of Cancer Program, led the University of Minnesota Cancer Center research team. Their work focused on cancer gene discovery in solid tumors using transposon-based techniques.

"Current cancer gene identification methods, such as microarrays, give correlations typically of thousands of genes, and it's hard to know from the correlations which genes relate to cancer and which do not," said Largaespada. "By comparison, the jumping gene has inserted itself into cancer genes in the tumors we studied and thereby allows us to focus on smaller numbers of genes -- genes that we know are important to the genesis of tumors. The result is a quicker, more efficient and accurate identification of cancer-causing genes."

Nancy Jenkins, Ph.D., head of NCI's Molecular Genetics of Development, and Neal Copeland, Ph.D., head of the Molecular Genetics of Oncogenesis in the Mouse Cancer Genetics program, led the NCI research team, which investigated the use of a highly mobile Sleeping Beauty transposon system to study lymphomas, a cancer that strikes the immune system.

"Although our discovery was made in laboratory mice," said Jenkins, "we believe that the technology used will reveal new insights into human cancer and could be translated for clinical use. Hopefully, this discovery will speed up the development of new drugs and improve already-in-use drugs that target specific genes for treatment of various types of cancer, including lymphomas.

The outcome of the new Sleeping Beauty method could be a major leap forward in understanding cancer's weak points and thus lead to better treatments."

According to Largaespada, "About 300 human cancer-related genes have thus far been reported in the scientific literature. Most of those identified are involved in cancers of the blood system. So, there are likely to be many more cancer genes that still need to be identified."

Additionally, he noted that the Sleeping Beauty technology is capable of providing important information about the genes that current methods do not -- such as the specific combinations of mutant genes that can work together to cause cancer. "With this information, we will understand the development of tumors at the genetic level in much finer detail," he said. "This is important because no single kind of cancer is going to be cured by one drug; it is going to take a combination of drugs to attack the pathways that are required for cancer to start and continue growing."

The next step for Largaespada, Jenkins, Copeland and their colleagues will be to generate and analyze a large number of other tumors induced in mice using the Sleeping Beauty jumping gene. Largaespada and his team will focus on identifying genes causing prostate, lung and colorectal cancer; Jenkins and her team will study genes for tumors in the brain, melanoma, breast, leukemia and lymphoma.

Largaespada, Jenkins and Copeland acknowledge the difference between research in mice and actual use in humans. But as Largaespada pointed out, "We have proof of principle that we're on the right track. We know that some of the same genes that are mutated in cancer in mice using Sleeping Beauty are also mutated in the same form of cancer in humans. An example is the Notch1 gene, which was mutated in 50 percent of mice with T cell lymphoma induced by Sleeping Beauty. The same gene is mutated in about 50 percent of people with a similar type of cancer. We believe the Sleeping Beauty method will allow us to identify many other such genes for other cancers."